Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-30
2002-11-26
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S127000, C546S130000
Reexamination Certificate
active
06486323
ABSTRACT:
TECHNICAL FIELD
This invention relates to a process for producing an optically active tropinonemonocarboxylic acid ester derivative which is an intermediate for synthesis of alkaloids having the same optically active tropane skeleton as the skeleton of cocaine having affinity for dopamine receptors or dopamine transporters as a pharmacological action.
BACKGROUND ART
In recent years, as the span of human life extends, patients with psychoneurotic diseases such as Parkinson's disease, Alzheimer's disease, etc. increase rapidly with a growth of the aged population, and the investigation of the cause of these psychoneurotic diseases and the establishment of therapeutic methods for them are accelerated at present. Parkinson's disease is chronic and progressive and their main symptoms are tremor, myoatrophy, akinesia, and impediment in posture maintenance. This diseases is caused by the loss of the balance between dopaminergic nervous system and cholinergic nervous system which is attributable to a marked decrease in the dopamine content of the striata body and substantia nigra of extrapyramidal motor system.
Therefore, in order to treat, for example, Parkinson's disease, it is necessary to supply the dopamine deficiency or control the cholinergic nervous system in an excited state.
On the other hand, cocaine is an alkaloid contained in leaves of, for example, Erythroxylon coca of South America growth, and was clinically used as a local anesthetic in 1877 for the first time by Koller. Cocaine has recently been found to have affinity for dopamine receptors or dopamine transporters, and it is being revealed that cocaine derivatives are useful as various tracer ligands. The basic structure of cocaine is its tropane skeleton. When cocaine is used as a starting material for a cocaine derivative, an optically active tropane skeleton having the same absolute configuration as that of the skeleton of natural (−)-cocaine can easily be derived as shown in the following reaction scheme A (A. P. Kozikowski, J. Med. Chem. 1995, 38, 3086):
As derivatives thus synthesized by using (−)-cocaine as a starting material, there are, for example, 2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)-tropane (&bgr;-CIT; U.S. Pat. No. 5,310,912) and its derivative 2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane (&bgr;-CIT-FP; WO 96/39198) which have affinity for dopamine transporters and are noted as diagnotic drugs for Parkinson's disease; (−)-ferruginine, an agonist for nicotine-like acetylcholine receptors; and (+)-knightinol.
Cocaine, however, is designated as a narcotic because of problems such as drug dependence, and there are various difficulties in obtaining and handling cocaine. Therefore, it is desirable to develop an economical and easy synthetic process of a cocaine analogue.
Attempts have been made to synthesize cocaine analogues since early times. Robinson et al. synthesized tropinone by condensing succindialdehyde with methyl amine and ethyl acetonedicarboxylate (Robinson R., J. Chem. Soc. 1917, 762-768). In 1991, anhydroecgonine methyl ester was synthesized from vinyldiazomethane and a pyrrole derivative by using a rhodium catalyst (Hum M. L. Davies et al., J. Org. Chem. 1991, 56, 5696-5700, Japanese Patent Application Kohyo No. 7-504665). The cocaine analogues synthesized by these processes are not optically active. As the synthesis of an optically active cocaine analogue, there is a case where (R)-allococaine or (R)-allopseudococaine was synthesized by saponifying cocaine or using as an intermediate, (R)-pseudoecgonine methyl ester obtained by optical resolution of (RS)-2-carbomethoxy-3-tropinone (F. I. Carroll et al., J. Med. Chem. 1991, 34, 883-886).
An example of enantio-selective asymmetric reaction without optical resolution is the syntheses of an optically active tropinonemonocarboxylic acid ester and anhydroecgonine methyl ester by the asymmetric synthetic reaction of tropinone with chiral lithium amide (Majewski M., J. Org. Chem. 1995, 60, 5825-5830). The thus obtained anhydroecgonine methyl ester, however, has an absolute configuration different from that of anhydro-ecgonine methyl ester derived from natural (−)-cocaine.
DISCLOSURE OF THE INVENTION
In view of such conditions, the present invention is intended to provide a process for producing an optically active tropinonemonocarboxylic acid ester derivative useful as an intermediate for synthesizing an optically active tropane derivative without using cocaine as a starting material.
The present invention relates to a process for producing an optically active tropinonemonocarboxylic acid ester derivative which comprises subjecting a tropinonedicarboxylic acid ester derivative represented by the following formula (1):
wherein R′ is an alkyl group, an aralkyl group or an amino-protecting group selected from lower aliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R is an alkyl group or an aralkyl group, to asymmetric dealkoxycarbonylation in the presence of an enzyme to obtain an optically active tropinonemonocarboxylic acid ester derivative represented by the following formula (2):
wherein R and R′ are as defined above.
The present invention also relates to a process for producing an optically active tropinonemonocarboxylic acid ester derivative which comprises reacting succindi-aldehyde represented by the following formula (3):
with an organic amine represented by the following formula (4):
R″—NH
2
(4)
wherein R″ is an alkyl group or an aralkyl group, and an acetonedicarboxylic acid ester represented by the following formula (5):
wherein R is an alkyl group or an aralkyl group; if necessary, converting the substituent derived from the substituent R″ of the organic amine of the formula (4) to an amino-protecting group; thereby obtaining a tropinonedicarboxylic acid ester derivative represented by the following formula (1):
wherein R′ is an alkyl group, an aralkyl group or an amino-protecting group selected from lower aliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R is an alkyl group or an aralkyl group; and then subjecting the tropinonedicarboxylic acid ester derivative to asymmetric dealkoxycarbonylation in the presence of an enzyme to obtain an optically active tropinonemonocarboxylic acid ester derivative represented by the following formula (2):
wherein R and R′ are as defined above.
The present invention further relates to a process for producing an optically active anhydroecgonine carboxylic acid ester derivative which comprises converting the substituent R′ and/or substituent R of the optically active tropinonemonocarboxylic acid ester derivative of the above formula (2) to another substitu-ent or other substituents if necessary, reducing the oxo group at the 3-position of this derivative, and then dehydrating the resulting compound to obtain an optically active anhydroecgonine carboxylic acid ester derivative represented by the following formula (6):
wherein R and R′ are as defined above.
BEST MODE FOR CARRYING OUT THE INVENTION
The optically active tropinonemonocarboxylic acid ester derivative obtained by the production process of the present invention is useful as an intermediate for synthesizing a cocaine analogue without using cocaine as a starting material, said cocaine analogue having a tropane skeleton, the basic ring structure of cocaine, and having the same optical activity as that of a cocaine analogue derived from natural (−)-cocaine.
The tropinonedicarboxylic acid ester derivative of the above formula (1), the starting material in the production process of the present invention, may be synthesized by the process shown in the following reaction scheme B:
As shown in the reaction scheme B, the tropinonedicarboxylic acid ester derivative of the formu
Nakamura Daisaku
Nakamura Soichi
Node Manabu
Desai Rita
Nihon Medi+Physics Co., Ltd.
Rotman Alan L.
Sughrue & Mion, PLLC
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